Compounds and methods for preparing methanesulfonamides

ABSTRACT

A process for preparing (S)-(-)-N-[4-[4-[ethyl(6-fluoro-6-methylheptyl)amino]-1-hydroxy]phenyl]methanesulfonamide hemifumarate salt, which comprises reacting N-[4[(2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide (IIa) with fluoroamine (III) in the presence of triacetoxyborohydride and ethyl acetate to provide [4-[4-[ethyl(6-fluoro-6-metylheptyl)amino]-1-hydroxy]phenyl]methanesulfonamide (I) anll then converting I into the hemifumarate salt Ia. A process for preparing IIa is also claimed as well as intermediates IIa-lId.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to a process and compounds useful for thepreparation of methanesulfonamides. In particular, it relates to aprocess and compounds useful for the preparation of(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl] methanesulfonamide hemifumarate salt. Thissalt is disclosed in U.S. Pat. No. 5,405,997 as a Class IIIantiarrhythmic compound which selectively prolongs the action potentialduration and concomitantly increases the refractory period of heartcells without significant effects on cardiac condition. The essentialparts of U.S. Pat. No. 5,405,997 are herein incorporated by reference.

[0003] 2. Prior Art

[0004] The process described for preparing(S)-(-)-N-[4-[4-ethyl(6-flouro-6-methyl-heptyl)amino-1-hydroxybutyl]phenyl]methanesulfonamidehemifumarate salt in U.S. Pat. No. 5,405,997 involved introduction ofthe fluoroamine moiety early in the synthesis. This results in theformation of a commercially unacceptable number of impurities.

[0005] The use of sodium triacetoxy borohydride for reductive aminationof utilizing 1,2-dichloroethane, tetrahydrofuran or acetonitrile assolvents is described in Abdel-Magid, A. F. et al, J. Org. Chem. 1996,61, 3849-3862.

[0006] The direct conversion of a hydroxy ester to a lactone employingbasic conditions with no loss in chiral purity was reported by Corey. E.J. et al, J. Am. Chem. Soc. 1987, 109, 7926-7927. However, whensubjected to the same basic conditions, hydroxy ester IIc of thisinvention resulted in a lactone that was racemic.

[0007] The use of the enzyme porcine pancreatic lipase to converthydroxy ester to lactones is also known, Gutman, A. L. et al, J. Org.Chem., 1990, 55, 3546-3552. The conversion of hydroxy acids to lactonesunder acidic conditions is described by Thompson, A. L. et al,Tetrahedron Lett. 1990, 31, 6953-6956. When the hydroxy ester of thisinvention is subjected to the ester hydrolysis of Thompson et al, acomplex mixture is obtained.

[0008] Lactonization of hydroxy esters under acidic conditions has alsobeen reported by Sibi, M. et al, Tetrahedron Let 1992, 5681-5684.Williams et al, Tetrahedron Let, 1989, 1331-1334 and Mohr, P. et al,Helv. Chim. Acta 1987, 142-152.

[0009] The complex interaction of physical properties that define thecapacity of a compound for upgrading (resolution) was described byJacques, J. et al, “Enantiomers Racemates and Resolutions”, John Wiley &Sons, New York, 1981.

OBJECT OF THE INVENTION

[0010] An object of this invention is to provide novel processes andnovel compounds for producing(S)-(-)-N-[4-[4-ethyl(6-flouro-6-methyl-heptyl)amino-1-hydroxybutyl]phenyl]methanesulfonamidehemifumarate salt.

[0011] Another object of the invention is to provide a process fordirect conversion of a hydroxy ester to a lactone without racemizationof the chiral center.

[0012] Still another object is the utilization of crystallization toupgrade the chiral purity of some of the novel compounds of thisinvention.

[0013] A further object of the invention is to provide a new process forpreparing(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide by reductive amination.

SUMMARY OF THE INVENTION

[0014] This invention provides a process for producing(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide hemifumarate salt (Ia) which comprises reactingN-[4-[(2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl] methanesulfonamide(IIa) with fluoroamine (III) in the presence of sodium triacetoxyborohydride and ethyl acetate to yield(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyllphenyl]methanesulfonamide (I) and then converting it to(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl] methanesulfonamide hemifumarate salt.

[0015] Further provided is the process defined above, whereinN-[4[(2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl] methanesulfonamide isprepared by (1) subjecting 4-[(methylsulfonyl)amino]-

-oxobenzenebutanoic acid(IIe) to a Fisher esterification to obtainmethyl 4[(methylsulfonyl)amino]-

-oxobenzenebutanoate (IId), (2) reducing methyl4-[(methylsulfonyl)amino]-

-oxobenzenebutanoate with (-)-DIP-Cl to obtain methyl (

S)-4-[methylsulfonyl)amino]-

-hydroxybenzenebutanoate (IIc), (3) subjecting methyl (

S)-4-[methylsulfonyl)amino]-

-hydroxybenzenebutanoate to lactonization with an acid catalyst in thepresence of a solvent at a temperature of between −10° to 23° C. toobtain N-[4-[(2S)-tetrahydro-5-oxo-2-furanyl]phenyl]methanesulfonamide(IIb) and (4) reactingN-4-[(S)-tetrahydro-5-oxo-2-furanyl]phenyl]methanesulfonamide withDIBAL-H⁻ in the presence of a solvent and at a temperature of between−35 to −30° C. to obtainN-[4-[(2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide(IIa).

[0016] Further provided is a compound having the formula

[0017] wherein R is selected from the group consistingof

[0018] (a) —C(O)—(CH₂)₂—C(O)—OCH₃

[0019] (b) —CH(OH)—(CH₂)₂—C(O)OCH₃

[0020] (c) 5-oxo-2-furanyl-

[0021] (d) 5-hydroxy-2-furanyl-.

[0022] Still further provided is a compound,N-ethyl-6-methyl-6-fluoroheptane amine.

[0023] Finally provided is a process for preparingN-ethyl-6-methyl-6-fluoroheptane amine which comprises reacting asolution of 6-bromo-2-fluoro-2-methylheptane with aqueous ethylamine andrecoveringN-ethyl-6-methyl-6-fluoroheptane amine from the reactionmixture.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention provides a process and compounds forpreparing(S)-(-)-N-[4-[4-ethyl(6-flouro-6-methyl-heptyl)amino-1-hydroxybutyl]phenyl]methanesulfonamidehemifumarate salt.

[0025] Before proceeding further with a description of the preferredembodiments of the present invention, a number of terms will be defined:

[0026] “DIBAL-H” means “diisobutylaluminum hydride”.

[0027] “DIP-Cl” means “(-)-p-chlorodiisopinocampheyl-borane”.

[0028] “EE” means “enantiomeric excess”.

[0029] “EtOAc” means “ethyl acetate”.

[0030] “GC” means “gas chromatography”.

[0031] “GT” means “greater than”.

[0032] “LT” means “less than”.

[0033] “Ms” means “CH₃SO₂—”.

[0034] “MTBE” means “tert-butylmethyl ether”.

[0035] “NMT” means “not more than”.

[0036] “RBF” means “round bottom flask”.

[0037] “THF” means “tetrahydrofuran”.

[0038] An embodiment of the process of the invention is illustrated inthe following schematic representation:

[0039] Step 1 involves the Fischer esterification of the compound ofFormula IIe to obtain the compound of Formula IId, a suitable compoundfor asymmetric reduction.

[0040] The compound of Formula IIe is either commercially available orcan be made by methods well known in the art.

[0041] Step 2 involves the installation of the chiral secondary alcohol,which is accomplished by using (-)-DIP-Cl as the asymmetric reductant togive the hydroxy ester of Formula IIc.

[0042] In Step 3, the hydroxy ester of Formula IIc is subjected tolactonization in the presence of an acid catalyst and a solvent to yieldthe lactone of Formula IIb. Acids such as hydrochloric, trichloroacetic,trifluoroacetic, p-toluenesulfonic and acetic acid can be used, but thepreferred acids are p-toluenesulfonic, trichloroacetic andtrifluoroacetic acids. Temperature is critical in this reaction. Thewashes must be done cold (0-5° C.) to avoid racemization.

[0043] Solvents include ethyl acetate, aceto nitrile, dichloromethaneand tetrahydrofuran. Dichloromethane and tetrahydrofuran are preferred.

[0044] While the lactonization can be conducted at temperatures of from−10° to 23° C., the higher temperature range leads to erosion or loss ofchiral purity. The preferred temperature is 0 to 5° C.

[0045] Step 4 involves the reduction of the lactone of Formula IIb withDIBAL-H in the presence of a solvent at a temperature of between −78° to0° C. to yield lactol IIa. The preferred range is −35° C. to −30° C.Solvents include toluene either alone or with a co-solvent. Thepreferred solvent is 1:1 methylene chloride/toluene. Over-reduction ofthe lactone to diol can be minimized by controlling theaddition rate ofthe DIBAL-H between 0.1 and 2.0 ml/min. The preferred rate is 0.5 to 1.0ml/min. While the reaction ratio will proceed with less than twoequivalents per equivalent of lactone, it will be slowed. The preferredstoichiometric ratio is 2.3 equivalents.

[0046] Since an excess of DIBAL-H is used, a prequench with ethylacetate is used to consume the reagent prior to aqueous workup. Theamount of ethyl acetate was 1.8 equivalents based on DIBAL-H used.Following the ethyl acetate prequench, the cold reaction mixture wasadded to a precooled solution of aqueous disodium citrate and thensubjected to an extractive work up with ethyl acetate to provide lactolIIa.

[0047] The lactol was capable of very efficient chiral upgrading bycrystallization from ethyl acetate (1 g/6 mL). Although the mostdesirable situation was to maintain high chiral purity throughout theentire route, significant upgrading was available if necessary. Forexample, lactone of 70% ee was converted to lactol having GT 98% ee. Theyield was directly related to the level of upgrading required.

[0048] Step 5 involves the reductive amination of lactol IIa withfluoroamine III and sodium triacetoxyborohydride in the presence ofethyl acetate. The temperature can range from 0° C. to 25° C. Thepreferred temperature range is 0 to 5° C. The starting materials forpreparing flouroamine III are commercially available or can be made bymethods well known in the art.

[0049] Fluoroamine III is prepared by reacting a solution comprising6-bromo-2-fluoro-2-methylheptane in a solvent, such as THF, with aqueousethylamine and recovering fluoroamine from the reaction mixture.

[0050] Step 6 involves reacting the compound of Formula I with fumaricacid in the presence of a solvent in accordance with methods well knownin the art for preparing pharmaceutically acceptable salts to yield(S)-(-)-N-[4-[4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfondamidehemifumurate salt Ia.

Preparation 1

[0051] Methyl-4-[(methylsulfonyl)amino]-

- oxobenzenebutanoate (Ild)

[0052] 4-[(methylsulfonyl)amino]

-oxobenzenebutanoic acid IIe, (125 g, 0.46 mol) was placed in a flaskwith 2.5 L of methanol, and 4.6 g of concentrated sulfuric acid (0.047mol) was added. The slurry was heated to 60° C. for 4 hr, during thisperiod the solids went into solution. After 4 hrs, an aliquot wasremoved to monitor completion by HPLC. The reaction was determinedcomplete when NMT 2% of the starting material remained. The solution wascooled to 21° C., allowing the product to crystallize. The slurry wascooled to 0° C., and the product was collected by filtration. The filtercake was washed with a mixture of 375 ml of methanol and 12.5 ml oftriethylamine (x2), followed by 375 mL of methanol. The title productwas obtained in 92% yield (99 area %) Melting point 181-183° C. ¹H NMR(400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.30 (d,J=8.8 Hz, 2H), 3.58 (s, 3H), 3.37 (s, 1H), 3.24 (t, J=6.4 Hz, 2H), 3.1(s, 3H), 2.63 (t, J=6.4 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ C 196.8,172.8, 143.0, 131.0; CH 129.6, 117.5; CH₂ 32.7, 27.6; CH3 51.3, 39.8; MSm/z calcd for C₁₂H₁₄NO₅S 284.31 (M-H)⁺; found 284.00 (M-H)⁺.

Preparation 2

[0053] Methyl(

S)-4-[(methylsulfonyl)amino]-

-hydroxybenzenebutanoate (IIc)

[0054] Methyl 4-[(methylsulfonyl)amino]-

-oxobenzene-butanoate from Preparation 1 was placed into a 1L flaskfitted with mechanical stirring and temperature probe. Tetrahydrofuran(2000 ml) was added to form a slurry. In a nitrogen box, (-)-DIP-Cl(362.6 g, 1.130 mol, 2.15 equiv) was weighed into an addition funnel anddissolved in 500 ml of tetrahydrofuran. The addition funnel was fittedto the flask and the system was flushed with nitrogen. The slurry in theflask was cooled to 0° C., and the DIP-Cl solution was added dropwise.There was very little exotherm. The addition can go fast as long as pottemp. was kept at about 0° C. The reaction was stirred for 72-96 hoursat 0° C. Monitored by HPLC (conditions below) for completion (LT 1%methyl ester). The slurry turned into a clear, colorless solution as thereaction progressed.

[0055] When the reaction was determined complete, acetone was added (200ml, 6 equiv) to quench the reaction. The mixture was stirred at 0° C.for an hour, then it was warmed to 23° C. The mixture was washed with a50% aqueous solution of NaHCO₃ (3×1000 ml). (Note: Significant formationof CO₂ gas!) The combined aqueous phase was extracted with MTBE (2×1000ml). The organics were combined and washed with 1000 ml brine. Thesolution was concentrated under reduced pressure, then swapped to MeOHunder reduced pressure to a final volume of 1500 ml. This MeOH solutionwas washed with heptanes (4×1000 ml). The MeOH solution was thenconcentrated under reduced pressure and swapped to CH₂Cl₂ for a finalvolume of less than 1000 ml. Washed the solution with 1000 ml brineanddried through a plug of MgSO₄. This solution was cooled (−15° C.) topromote crystallization. (Note: A slight vacuum may be applied ifnecessary, but only until solids begin to crystallize.) Hold theresulting slurry at −15° C. for 3-4 hours. The product was collected byfiltration, using heptanes to rinse flask and wash cake, and dried onnitrogen press. The title product was obtained as white, powdery solid(132.5 g, 88% yield). Melting point 70-72° C. ¹H NMR (400 MHz, CDCl₃) δ7.09 (d, J=8.4 Hz, 2H), 6.96 (dd, J=4.9, 8.4 Hz, 2H), 4.51 (dd, J=6.3,6.4 Hz, 1H), 3.45 (s, 3H), 2.77 (s, 3H), 2.21 (t, J 7.2 Hz, 2H), 1.81(dt, J=6.8, 6.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ C 174.4, 141.2,136.1; CH 127.1, 120.9, 72.8; CH₂ 33.7, 30.3; CH₃ 51.8, 39.2; MS m/zcalcd for C₁₃H₁₉NO₅S, 286.075 (M-H)⁺; found 285.94 (M-H)⁺.

Preparation 3

[0056] N-[4-[(2S)-Tetrahydro-5-oxo-2-furanyl]phenyl]methanesulfonamide(IIb)

[0057] Methyl(

S)-4-[(methylsulfonyl)amino]-

-hydroxybenzenebutanoate (17.9 g, 62.3 mmol) from Preparation 2 wasplaced in a flask with 350 ml of CH₂Cl₂ and the resulting slurry wascooled to 0° C. To this mixture was added 0.12 g of p-TsOH.H₂O (1.5mol%). The reaction wasmonitored for completion by HPLC until NMT 2%hydroxy ester remained (expect 4-6 h). The reaction mixture was washedwith H₂O (2×250 ml) and brine (250 ml) while maintaining the temperatureat 0° C. The pH of the final wash must be maintained at GT 5). Theorganic layer was dried with MgSO₄, filtered and concentrated underreduced pressure. The resulting solids were recrystallized from EtOAc(25 ml) to provide 12.1 g (76% yield) of the title compound as whitesolids (95 area %, 97% ee) . Melting point 101-102° C. ¹H NMR (400 MHz,CDC1₃) δ 7.24 (dt, J=8.0, 8.6 Hz, 4H), 5.43 (m, 1H), 2.97 (s, 3H), 2.63(m, 3H), 2.14 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ C 177.0, 137.2, 136.0;CH 126.8, 120.7, 80.9; CH₂ 30.7, 29.0; CH₃ 39.4; MS m/z calcd forC₁₁H₁₃NO₄S, 255.056 (M⁺); found 254.95 (M⁺).

Preparation 4

[0058]N-[4-[(2S)-Tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide(IIa)

[0059] N-[4-[(2S)-Tetrahydro-5-oxo-2-furanyl]-phenyl]methanesulfonamide(IIb) from Preparation 3 (9.823 g, 38.5 mmol) was dissolved in aCH₂Cl₂/toluene (100 ml/41 ml) at 23° C., then cooled to −30° C. Themixture was a slurry. DIBAL-H (59 ml, 1.5 M in toluene) was added slowlyto the mixture (1 ml/min). After addition was complete, the solution wasstirred until less than 1% of lactone remained by HPLC assay. When thereaction was complete, excess DIBAL-H was pre-quenched with EtOAc (15ml). This mixture was then added to a pre-cooled (0° C.) aqueoussolution of disodium citrate (1.0 M, 200 ml). The reaction mixture wasnot allowed to warm during this addition period. Ethyl acetate (200 ml)was added, and the resulting two-phase mixture was stirred for at least5 hours. The organic layer was separated, and the aqueous layer wasextracted with EtOAc (2×100 ml). The combined organic layers were washedwith brine (2×150 ml). The solvent was removed under reduced pressure.The crude solids were crystallized from ethyl acetate (6 mL/g). A whitesolid was obtained (8.04 g), having 3% diol by area. Recrystallizationfrom ethyl acetate provided 6.4 g of the title product as a white,powdery solid (64% yield, 93 area %, GT 99% ee). Melting point=129-130°C. ¹H NMR (400 MHz, CD₃OD) δ 7.42 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz,1H), 7.29 (d, J=8 Hz, 1H), 7.21 (d, J=8.1 Hz, 2H), 5.65 (m, 0.5H), 5.53(m, 0.5 H), 5.14 (t, J=6.9 Hz, 0.5 H), 4.93 (t, J=7.6 Hz, 0.5 H), 2.92(s, 3H), 2.49 (m, 1H), 2.25 (m, 1H), 1.98 (m, 1H), 1.92 (m, 1H); ¹³C NMR(100 MHz, CD₃OD) δ C 142.9, 141.2, 140.6, 138.6, 138.5; CH 128.4, 127.9,121.7, 191.6, 99.9, 99.5, 83.2, 80.3, 74.4, 74.3; CH₂ 35.5, 35.1, 34.4,34.2, 33.9; CH₃ 39.1, 39.0. MS (EI) m/z calcd for C₁₁H₁₅NO₄S 257.07(M⁺).

Preparation 5

[0060] 7-bromo-2-hydroxyl-2-methylheptane

[0061] A first reaction vessel was charged with ethyl 6-bromohexanoate(175 g) and the line was rinsed with 177 g of THF. The solution cooledto −20° C. A second reaction vessel was charged with 2-M methylmagnesium chloride in THF (902 g). The solution was cooled to −20° C.The 6-bromohexanoate solution was transferred to the second reactionvessel keeping the temperature in the second reaction vessel less than10° C. The first reaction vessel was rinsed with 50 g of THF. Thereaction was assayed by GC (15 m DB-1 0.25 micron ID column. 70° C. for5 minutes to 275° C. at 20° C./min with injector at 140° C. and detectorat 250° C.) until less than 2% of starting material remained.

[0062] Water (580 ml) was charged to the first reaction vessel followedby concentrated HCl (192 g). The solution was cooled to 10-15° C. Thereaction mixture was transferred to the acid solution keeping thetemperature less than 20° C. Toluene (920 ml) was added and the phaseswere separated. The aqueous phase was back extracted with toluene (200ml) and discarded. The combined organic phases were washed withsaturated sodium chloride (700 ml). The7-bromo-2-hydroxyl-2-methylheptane could be isolated by distillation ofthe solvent under reduced pressure.

[0063] C₈H₁₇BrO

[0064]¹H NMR (400 MHz, CDCl₃) δ 3.38 (t, J =7.8 Hz, 2 H), 1.78 (m, 2 H),1.58 (m, 2 H), 1.3 (m, 4 H), 1.20 (s, 6 H); ¹³C NMR (100 MHz, CDCl₃) δ70.9, 42.8, 33.7, 33.2, 29.5, 27.9, 22.8.

Preparation 6

[0065] 6-bromo-2-fluoro-2-methylheptane

[0066] 500 ml of branched octanes (commercially available) and anhydrousHF (110 g) were charged to a reaction vessel and the mixture cooled to−20 to −30° C. A solution of 7-bromo-2-hydroxyl-2-methylheptane (281 g)in branched octanes (1000 ml) was added to the HF and stirred at −20 to−30° C. for 7 hours. A sample was tested at 20° C./min with injector at140° C. and detector at 250° C.) and showed less than 0.5% of thestarting alcohol. The reaction was quenched by addition in a solution ofpotassium carbonate (1906 g) in water (1800 ml). The phases wereseparated and the organic distilled to a volume of 500 ml. The6-bromo-2-fluoro-2-methylheptane could be isolated by vacuumdistillation or carried directly into the next reaction.

[0067]¹H NMR (400 MHz, CDCl₃) δ 3.38 (t, J=16 Hz, 2 H), 1.78 (m, 2 H),1.59 (d of t, J=24Hz J=8 Hz, 2 H), 1.48 (m, 2 H), 1.35 (d, J=24 Hz, 6H); 13C NMR (100 MHz, CDCl₃) 8 99.6 (d, J=45 Hz), 41.1 (d, J=16 Hz),33.7, 33.2, 27.9, 27.1, 22.5. MS (ESI+) for C₈H₁₆BrF m/z 212 (M+H)⁺.Anal Calcd for C₈H₁₆BrF: C, 45.51; H, 7.64; F, 9.0; Br, 37.85; found: C,45.65; H, 7.76; F, 8.94.

Preparation 7

[0068] N-ethyl-6-methyl-6-fluoroheptane amine [0039) The6-bromo-2-fluoro-2-methylheptane solution prepared in Preparation 6 (283g) was charged to a reaction vessel. The solution was concentrated to450 ml by vacuum distillation and THF (765 g) was added followed by 70%aqueous ethylamine (557 g). The reaction was stirred at 30-35° C for 6hours. The reaction was cooled and water (900 ml) and methylene chloride(900 ml) were added. The phases were separated and the aqueous backwashed with methylene chloride (900 ml). The combined organic layerswere washed with water (450 ml) and concentrated to a volume of 450 mlby vacuum distillation. THF (810 g) was added and the solutionconcentrated to a volume of 450 ml. This solvent displacement wasrepeated and the N-ethyl-6-methyl-6-fluoroheptane amine packaged as aTHF solution.

[0069]¹H NMR (400 MHz, CDCl₃) δ 2.66 (t, J=4 Hz, 2 H), 2.61 (q, J=8 Hz,2 H), 1.48 (m, 2 H), 1.42 (m, 2 H), 1.38 (m, 2 H), 1.34 (d, J=24 Hz, 6H), 1.15 (t, J=8 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 99.6 (d, J=43 Hz),49.0, 44.4, 41.6 (d, J=23 Hz), 28.13, 27.9, 27.1, 21.9, 15.52. AnalCalcd for C₁₀H₂₂FN: C, 68.52; H, 12.65; F, 10,84; N, 7.99; found: C,68.65; H, 12.66; F, 10.89, N, 7.80.

Example 1

[0070](S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide(I)

[0071]N-[4-[(2S)-Tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide(10.0 g, 38.9 mmol) from Preparation 4 andN-ethyl-6-methyl-6-fluoroheptane amine (99% pure, 6.8 g, 38.9 mmol) fromPreparation 7 were stirred with EtOAC (25 ml) in a flask for 1 hour. Theslurry became clear solution, indicating formation of the iminium salt.Sodium triacetoxyborohydride (11.5 g, 54.4 mmol) was placed in aseparate flask with EtOAc (50 ml). The mixture was cooled to 0° C. Thefirst solution (iminium salt) was added slowly to the second mixturewith vigorous stirring. The temperature was maintained at 0 to 4° C.After the addition was complete, the flask was rinsed with EtOAc (10ml), and that was added also. The mixture was stirred overnight at 0° C.Water (100 ml) was added to quench the excess reagent, while thetemperature was maintained at 0 to 4° C. While cooling was maintained,the pH was raised to 6.5 using a 10% aqueous sodium hydroxide solution.The layers were separated, and the aqueous was extracted with EtOAc(2×50 ml). The aqueous layer was then adjusted to pH 8.2, and theproduct was extracted with EtOAc (3×100 ml). The solvent was removedunder reduced pressure to provide the title product as a colorless oil(14.9 g) in 92% yield. TLC 100% EtOAc, Rf=0.15.

Example 2

[0072](S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide hemifumarate salt (Ia)

[0073] A 50 ml portion of(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide, from Example 1, ethyl acetate solution (contains7.78 g 18.7 mmol) was placed into a 100 ml RBF. The solvent was removedunder reduced pressure. Tetrahydrofuran (40 ml) was added, and thesolvent was removed under reduced pressure. Another 40 ml of THF wasadded, and the solution was concentrated to a volume of 15 ml. A 250 ml4-neck RBF was charged with fumaric acid (1.08 g, 9.34 mmol) and 80 mlof THF. This mixture was heated to 40 to 45° C., and the solids wentinto solution. The THF solution of(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide was added to the fumaric acid solution, rinsing with20 ml of THF. The mixture was stirred at 40 to 45° C. for 30 min., thenconcentrated to 45 ml under vacuum. The mixture was then heated toreflux (bath temp 75 to 80° C.) for 30 min., then cooled to 45 to 50° C.over a 30 min. period. To this was added 0.05 g of(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-l-hydroxybutyl]phenyl]methanesulfonamide hemifumarate salt (Ia) seed crystals. The mixture wasstirred at 45 to 50° C. for 15 min.

[0074] Using a syringe pump (0.6 ml/h), 14 ml of branched octane wasadded while maintaining the pot temperature at 45 to 50° C. The mixtureformed an oil rather than the expected solids, so another portion ofPNU-108342E seed crystals was added. The mixture was stirred at 45 to50° C. for 24 hours, and the mixture formed a thick slurry during thistime. A 60 ml coarse fritted filter was preheated to 45 to 50° C., andused to collect the solids. The cake was washed in two parts using amixture of 20 ml of THF and 5 ml of branched octane; then the cake waswashed in two parts using 25 ml of branched octane. The cake was driedin the vacuum oven at 40 to 45° C. The title compound was obtained as ahard cake of white solids (8.1 g, 17.3 mmol, 92%).

1. A process for preparing(S)-(-)-N-[4-[-4-(ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide (I) which comprises reactingN-[4[(2S)-tetrahydro-5-hydroxy-2-furanyllphenyl]methanesulfonamide (Ila)with flouroamine (III)in the presence of triacetoxy borohydride andethyl acetate.
 2. A process according to claim 1, wherein N- [4 [ (2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl] methanesulfonamide is preparedby (l)subjecting 4-[(methylsulfonyl)amino]-

-oxobenzenebutanoic acid(IIe) to a Fisher esterification to obtainmethyl 4[(methylsulfonyl)amino]-

-oxobenzenebutanoate (IId), (2) reducing methyl4-[(methylsulfonyl)amino]-

-oxobenzenebutanoate with (-)-DIP-CI to obtain methyl (

S)-4-[methylsulfonyl)amino] -

-hydroxybenzenebutanoate (IIc), (3) subjecting methyl(

S)-4-[methylsulfonyl)aminol-

-hydroxybenzenebutanoate to lactonization with an acid catalyst in thepresence of a solvent at a temperature of between −10° to 23° C. toobtain N-[4-[(2S)-tetrahydro-5-oxo-2-furanyl]phenyl]methanesulfonamide(Ilb) and reactingN-(4-[(2S)-Tetrahydro-5-oxo-2-furanyl]phenyl]methanesulfonamide withDIBAL-H in the presence of a solvent and at a temperature of between −35to −30 C obtainN-[4-[(2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl]methanesulfonamide. 3.A process according to claim 1, wherein(S)-(-)-N-[4-[-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyllphenyl]methanesulfonamide is further reacted with fumaric acid to obtain(S)-(-)-N-[4-(-4-[ethyl(6-fluoro-6-methyl-heptyl)amino]-1-hydroxybutyl]phenyl] methanesulfonamidehemifumarate salt.
 4. A compound having the formula

wherein R is selected from the group consisting of (a)—C(O)—(CH₂)₂—C(O)OCH₃ (b) —C(OH)—(CH₂)₂—C(O)OCH₃ (c) 5-oxo-2-furanyl-(d) 5-hydroxy-furanyl-.
 5. A compound according to claim 4, wherein R isselected from the group consisting of —C(O)—(CH₂)₂— C(O)OCH₃ and—CH(OH)—(CH₂)₂—C(O)OCH₃.
 6. A compound according to claim 5, methyl4-((methylsulfonyl)amino]-

-oxobenzenebutanoate.
 7. A compound according to claim 5, methyl (

S)-4-[methylsulfonyl)amino]-

-hydroxybenzene-butanoate.
 8. A compound according to claim 4, wherein Ris selected from the group consisting of 5-oxo-2-furanyl- and5-hydroxy-furanyl.
 9. A compound according to claim 8,N-[4-[(2S)tetrahydro-5-oxo-2-furanyl]phenyl]methane-sulfonamide.
 10. Acompound according to claim 8,N-[4-[(2S)-tetrahydro-5-hydroxy-2-furanyl]phenyl]methane-sulfonamide.11. A fluoroamine compound, N-ethyl-6methyl-6-fluoroheptane amine.
 12. Aprocess for preparing N-ethyl-6-methyl-6-fluoroheptane amine whichcomprises reacting a solution of 6-bromo-2-fluoro-2-methylheptane withaqueous ethylamine in the presence of a solvent and recovering theN-ethyl-6-methyl-6-fluoroheptane amine from the reaction mixture.